{"doi":"10.3390/ijms25020980","title":"Caveolin-3 and Caveolin-1 Interaction Decreases Channel Dysfunction Due to Caveolin-3 Mutations","abstract":"<jats:p>Caveolae constitute membrane microdomains where receptors and ion channels functionally interact. Caveolin-3 (cav-3) is the key structural component of muscular caveolae. Mutations in CAV3 lead to caveolinopathies, which result in both muscular dystrophies and cardiac diseases. In cardiomyocytes, cav-1 participates with cav-3 to form caveolae; skeletal myotubes and adult skeletal fibers do not express cav-1. In the heart, the absence of cardiac alterations in the majority of cases may depend on a conserved organization of caveolae thanks to the expression of cav-1. We decided to focus on three specific cav-3 mutations (Δ62-64YTT; T78K and W101C) found in heterozygosis in patients suffering from skeletal muscle disorders. We overexpressed both the WT and mutated cav-3 together with ion channels interacting with and modulated by cav-3. Patch-clamp analysis conducted in caveolin-free cells (MEF-KO), revealed that the T78K mutant is dominant negative, causing its intracellular retention together with cav-3 WT, and inducing a significant reduction in current densities of all three ion channels tested. The other cav-3 mutations did not cause significant alterations. Mathematical modelling of the effects of cav-3 T78K would impair repolarization to levels incompatible with life. For this reason, we decided to compare the effects of this mutation in other cell lines that endogenously express cav-1 (MEF-STO and CHO cells) and to modulate cav-1 expression with an shRNA approach. In these systems, the membrane localization of cav-3 T78K was rescued in the presence of cav-1, and the current densities of hHCN4, hKv1.5 and hKir2.1 were also rescued. These results constitute the first evidence of a compensatory role of cav-1 in the heart, justifying the reduced susceptibility of this organ to caveolinopathies.</jats:p>","journal":"International Journal of Molecular Sciences","year":2024,"id":654925,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1709380,"name":"Elisabetta Gazzerro","orcid":"0000-0003-2428-0302","position":1,"is_corresponding":false},{"id":457103,"name":"Chiara Fiorillo","orcid":"0000-0001-9027-343X","position":2,"is_corresponding":false},{"id":1285050,"name":"Serena Baratto","orcid":"0000-0002-4633-4933","position":3,"is_corresponding":false},{"id":1709381,"name":"Chiara Bartolucci","orcid":"0000-0001-6231-2980","position":4,"is_corresponding":false},{"id":299677,"name":"Stefano Severi","orcid":"0000-0003-4306-8294","position":5,"is_corresponding":false},{"id":1709382,"name":"Raffaella Milanesi","orcid":null,"position":6,"is_corresponding":false},{"id":1709383,"name":"Melania Lippi","orcid":null,"position":7,"is_corresponding":false},{"id":1709384,"name":"Marianna Langione","orcid":"0000-0002-7783-2177","position":8,"is_corresponding":false},{"id":1709385,"name":"Carmen Murano","orcid":"0000-0003-3146-6754","position":9,"is_corresponding":false},{"id":1709386,"name":"Clarissa Meoni","orcid":null,"position":10,"is_corresponding":false},{"id":1709387,"name":"Vera Popolizio","orcid":null,"position":11,"is_corresponding":false},{"id":1709388,"name":"Alessandro Cospito","orcid":"0000-0002-8919-4889","position":12,"is_corresponding":false},{"id":1709389,"name":"Mirko Baruscotti","orcid":null,"position":13,"is_corresponding":false},{"id":1709390,"name":"Annalisa Bucchi","orcid":null,"position":14,"is_corresponding":false},{"id":1709393,"name":"Andrea Barbuti","orcid":"0000-0002-4521-4913","position":15,"is_corresponding":false},{"id":1709379,"name":"Patrizia Benzoni","orcid":"0000-0002-3371-3301","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Caveolin-3 and Caveolin-1 Interaction Decreases Channel Dysfunction Due to Caveolin-3 Mutations","abstract":"lead to caveolinopathies, which result in both muscular dystrophies and cardiac diseases. In cardiomyocytes, cav-1 participates with cav-3 to form caveolae; skeletal myotubes and adult skeletal fibers do not express cav-1. In the heart, the absence of cardiac alterations in the majority of cases may depend on a conserved organization of caveolae thanks to the expression of cav-1. We decided to focus on three specific cav-3 mutations (Δ62-64YTT; T78K and W101C) found in heterozygosis in patients suffering from skeletal muscle disorders. We overexpressed both the WT and mutated cav-3 together with ion channels interacting with and modulated by cav-3. Patch-clamp analysis conducted in caveolin-free cells (MEF-KO), revealed that the T78K mutant is dominant negative, causing its intracellular retention together with cav-3 WT, and inducing a significant reduction in current densities of all three ion channels tested. The other cav-3 mutations did not cause significant alterations. Mathematical modelling of the effects of cav-3 T78K would impair repolarization to levels incompatible with life. For this reason, we decided to compare the effects of this mutation in other cell lines that endogenously express cav-1 (MEF-STO and CHO cells) and to modulate cav-1 expression with an shRNA approach. In these systems, the membrane localization of cav-3 T78K was rescued in the presence of cav-1, and the current densities of hHCN4, hKv1.5 and hKir2.1 were also rescued. These results constitute the first evidence of a compensatory role of cav-1 in the heart, justifying the reduced susceptibility of this organ to caveolinopathies.","is_dataset_classified":null,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38256054","pmcid":"PMC10816214","openalex_id":"https://openalex.org/W4390788600","authors":[],"funders":[{"funder_name":"Fondazione CARIPLO","grant_id":"2014-1090","title":null},{"funder_name":"Ministry of Education, Universities and Research","grant_id":"Project PE_00000019 \"HEAL ITALIA\"","title":null},{"funder_name":"European Union—NextGenerationEU through the Italian Ministry of University and Research","grant_id":"Project PE_00000019 “HEAL ITALIA”","title":null}],"total_grants":3,"fwci":1.6496,"citation_percentile":0.80246269,"influential_citations":0,"citation_trend":[{"year":2024,"count":2},{"year":2025,"count":4},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/25/2/980/pdf?version=1705145272","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/25/2/980/pdf?version=1705145272","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms25020980","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38256054","host_type":"repository"},{"url":"https://hdl.handle.net/2434/1035510","host_type":"repository"},{"url":"https://hdl.handle.net/10281/487801","host_type":"repository"},{"url":"https://edoc.mdc-berlin.de/id/eprint/24039/2/24039suppl.zip","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10816214","host_type":"repository"},{"url":"https://www.mdpi.com/1422-0067/25/2/980","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/ijms25020980","host_type":"repository"},{"url":"https://air.unimi.it/bitstream/2434/1035510/2/ijms-25-00980-v2.pdf","host_type":"repository"},{"url":"https://boa.unimib.it/bitstream/10281/487801/1/Benzoni-2024-ijms-VoR.pdf","host_type":"repository"},{"url":"https://edoc.mdc-berlin.de/id/eprint/24039/1/24039oa.pdf","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10816214/pdf/ijms-25-00980.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10816214","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10816214?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Caveolin-1 and cellular processes","RNA Research and Splicing","Ion channel regulation and function","Adult","Animals","Cricetinae","Humans","Caveolin 1","Caveolin 3","Cricetulus","Mutation","CHO Cells","Ion Channels"],"mesh_terms":["Adult","Animals","Cricetulus","Cricetinae","Humans","Ion Channels","Mutation","CHO Cells","Caveolin 1","Caveolin 3"],"keywords":["Caveolae","Caveolin 3","Caveolin","Cell biology","Myogenesis","Ion channel","Myocyte","Biology","Caveolin 1","Mutant","Mutation","Intracellular","Skeletal muscle","Receptor","Chemistry","Signal transduction","Genetics","Anatomy","Gene","Electrophysiology","Caveolin-1","Kir2.1","Caveolin-3","Kv1.5","Hcn4","Caveolinopathies"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"alphafold"},{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T08:57:44.600121Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}